Age-related macular degeneration (AMD) is the leading cause of blindness in persons 65 years of age and older in the developed world. Multiple lines of evidence support an immunologic basis and genetic disposition for the development of AMD. In this context, human leukocyte antigen (HLA) polymorphisms, encoded within the major histocompatibility complex (MHC), and killer immunoglobulin-like receptors (KIR) are of particular interest. HLA and KIR genes are among the most polymorphic within the human genome and variation within these regions has not been comprehensively assessed as a risk factor for AMD. We propose to test the hypothesis that genetic variation at the HLA and KIR loci, comprehensively assayed using next generation high-throughput sequencing methods for massively parallel DNA sequencing, modulate susceptibility to AMD both individually and in combination (HLA-KIR epistasis). Because of the complexity of the HLA and KIR regions, standard genotyping techniques including genome- wide association studies do not properly discern the contribution of these regions to disease susceptibility. Our approach will overcome some of the limitations of previous association studies that have incompletely tested HLA and KIR genetic variation and neglected KIR gene copy number as a source of genetic variation. We will employ unique laboratory and statistical methods developed for HLA and KIR that account for the extensive linkage disequilibrium (LD) within these regions. We will assess the association between HLA and KIR sequence and copy number variation and AMD in a case-control study nested within the Study of Osteoporotic Fractures (SOF) cohort; a longitudinal, population-based study. The HLA and KIR regions will be genotyped from 570 AMD cases and 570 controls participating in the SOF-Eye study. Results will be replicated in 855 cases and 855 controls from additional population and family-based samples. The genotyping costs will be minimal compared to the costs of recruitment, interviewing, and DNA collection that already have been accomplished. We have assembled a diverse team of leading scientists and experts in the genetics of eye disease, epidemiology, and HLA-KIR genetics. Our experience with the HLA and KIR genotyping has allowed us to develop quality control measures for the genotyping technologies and databases for processing the data. Understanding the role of HLA and KIR genetic variation in AMD may identify individuals at risk for AMD and ultimately lead to opportunities to modulate these pathways by precise pharmacological means and thus improve visual outcomes in this devastating disease.